NDC Code Structure

NDC Product Information

Piperacillin And Tazobactam with NDC 61990-0140 is a a human prescription drug product labeled by Apollo Pharmaceuticals Inc.. The generic name of Piperacillin And Tazobactam is piperacillin sodium and tazobactam sodium. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Labeler Name: Apollo Pharmaceuticals Inc.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of piperacillin and tazobactam for injection and other antibacterial drugs, piperacillin and tazobactam for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.Piperacillin and Tazobactam for Injection is a combination product consisting of a penicillin-class antibacterial, piperacillin, and a β-lactamase inhibitor, Tazobactam, indicated for the treatment of patients with moderate to severe infections caused by susceptible isolates of the designated bacteria in the conditions listed below.

1.1 Intra-Abdominal Infections

Appendicitis (complicated by rupture or abscess) and peritonitis caused by β-lactamase producing isolates of

Escherichia coli or the following members of the

Bacteroides fragilis group:

B. fragilis,

B. ovatus,

B. thetaiotaomicron, or

B. vulgatus. The individual members of this group were studied in fewer than 10 cases.

P. aeruginosa should be treated in combination with an aminoglycoside) [

see Dosage and Administration (2)

].

1.6 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of piperacillin and tazobactam for injection and other antibacterial drugs, piperacillin and tazobactam for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 Dosage And Administration

Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

2.1 Adult Patients

The usual total daily dose of piperacillin and tazobactam for injection for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam). The usual duration of piperacillin and tazobactam for injection treatment is from 7 to 10 days.Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

2.2 Nosocomial Pneumonia

Initial presumptive treatment of patients with nosocomial pneumonia should start with piperacillin and tazobactam for injection at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam). The recommended duration of piperacillin and tazobactam for injection treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom

P. aeruginosa is isolated.

2.3 Renal Impairment

In patients with renal impairment (creatinine clearance 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for Injection should be reduced to the degree of actual renal function impairment. The recommended daily doses of piperacillin and tazobactam for injection for patients with renal impairment are as follows:Table 1: Recommended Dosing of Piperacillin and Tazobactam for Injection in Patients with Normal Renal Function and Renal-Impairment (As total grams Piperacillin/Tazobactam) * Creatinine clearance for patients not receiving hemodialysis​† ​0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodyalisis days.

†2.25 q 12 h2.25 q 8 hCAPD2.25 q 12 h2.25 q 8 hFor patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g piperacillin and tazobactam for injection (0.67 g Piperacillin/0.08 g Tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of piperacillin and tazobactam for injection is necessary for CAPD patients.

2.4 Pediatric Patients

For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended piperacillin and tazobactam for injection dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours. For pediatric patients between 2 months and 9 months of age, the recommended piperacillin and tazobactam for injection dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours [

see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.

It has not been determined how to adjust piperacillin and tazobactam for injection dosage in pediatric patients with renal impairment.

2.5 Reconstitution And Dilution Of Powder Formulations

Pharmacy bulk vialsReconstituted stock solution must be transferred and further diluted for intravenous infusion.The pharmacy bulk vial is for use in a hospital pharmacy admixture service only under a laminar flow hood. After reconstitution, entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and contents should be dispensed as aliquots into intravenous solution using aseptic technique. Use entire contents of pharmacy bulk vial promptly. Discard unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]).Reconstitute the pharmacy bulk vial with exactly 51mL (for 13.5 g vial) and 152 mL (for 40.5 vial) of a compatible reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.Shake well until dissolved. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to and during administration whenever solution and container permit.Compatible Reconstitution Diluents for Pharmacy Bulk Vials0.9% Sodium Chloride for Injection

Sterile Water for Injection

Dextrose 5%

Bacteriostatic Saline/Parabens

Bacteriostatic Water/Parabens

Bacteriostatic Saline/Benzyl Alcohol

Bacteriostatic Water/Benzyl Alcohol

Reconstituted piperacillin and tazobactam for injection solutions for pharmacy bulk vials should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below. Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.Compatible Intravenous Solutions for Pharmacy Bulk Vials0.9% Sodium Chloride for Injection

Sterile Water for Injection

​‡Dextran 6% in Saline

Dextrose 5%

LACTATED RINGERS SOLUTION IS NOT COMPATIBLE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION.‡ Maximum recommended volume per dose of sterile water for injection is 50 mL.

Piperacillin and tazobactam for injection should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.Piperacillin and tazobactam for injection is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.Piperacillin and tazobactam for injection should not be added to blood products or albumin hydrolysates. Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit.Stability of Piperacillin and Tazobactam for Injection Powder Formulations Following ReconstitutionPiperacillin and tazobactam for injection reconstituted from pharmacy bulk is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents. The pharmacy bulk vial should NOT be frozen after reconstitution. Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).Pharmacy bulk vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Vials should not be frozen after reconstitution.Stability studies in the I.V. bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature. Piperacillin and tazobactam for injection contains no preservatives. Appropriate consideration of aseptic technique should be used.Piperacillin and tazobactam for injection reconstituted from pharmacy bulk vials can be used in ambulatory intravenous infusion pumps. Stability of piperacillin and tazobactam for injection in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature. Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL. One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V. bags or cartridge). The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions. Stability of piperacillin and tazobactam for injection is not affected when administered using an ambulatory intravenous infusion pump.

2.7 Compatibility With Aminoglycosides

Due to the

in vitro inactivation of aminoglycosides by piperacillin, piperacillin and tazobactam for injection and aminoglycosides are recommended for separate administration. Piperacillin and tazobactam for injection and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [

see

Drug Interactions (7.1)].

In circumstances where co-administration via Y-site is necessary, piperacillin and tazobactam for injection is compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: Table 2: Compatibility with Aminoglycosides​Aminoglycoside​Piperacillin and Tazobactam for Injectyion Dose (grams)​Piperacillin and Tazobactam for Injection Diluent Volume (mL)​Aminoglycoside Concentration Range

1001500.7 - 3.320.9% sodium chloride or 5% dextrose​a​ The concentration ranges in Table 2 are based on administration of the aminoglycoside in divided doses (10-15 mg/kg/day in two daily doses for amikacin and 3-5 mg/kg/day in three daily doses for gentamycin). Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with piperacillin and tazobactam for injection has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions.

Only the concentration and diluents for amikacin or gentamicin with the dosages of piperacillin and tazobactam for injection listed above have been established as compatible for co-administration via Y-site infusion. Simultaneous co-administration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by piperacillin and tazobactam for injection.Piperacillin and tazobactam for injection is not compatible with tobramycin for simultaneous coadministration via Y-site infusion. Compatibility of piperacillin and tazobactam for injection with other aminoglycosides has not been established.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

3 Dosage Forms And Strengths

​Piperacillin and Tazobactam for Injection is supplied as a white to off-white powder in bottles of the following sizes:

Piperacillin and tazobactam for injection is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or β-lactamase inhibitors.

5.1 Hypersensitivity Adverse Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with piperacillin and tazobactam for injection. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with piperacillin and tazobactam for injection, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, piperacillin and tazobactam for injection should be discontinued and appropriate therapy instituted.

5.2 Severe Cutaneous Adverse Reactions

Piperacillin and tazobactam for injection may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and piperacillin and tazobactam for injection discontinued if lesions progress.

5.3 Hematologic Adverse Reactions

Bleeding manifestations have occurred in some patients receiving β-lactam drugs, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, piperacillin and tazobactam for injection should be discontinued and appropriate therapy instituted.The leukopenia/neutropenia associated with piperacillin and tazobactam for injection administration appears to be reversible and most frequently associated with prolonged administration.Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, ie, ≥ 21 days [see

Adverse Reactions (6.1)].

5.4 Central Nervous System Adverse Reactions

As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

5.5 Nephrotoxicity In Critically Ill Patients

The use of piperacillin and tazobactam for injection was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients [see

Adverse Reactions (6.1)]. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with piperacillin and tazobactam for injection [see

Dosage and Administration (2.3)].

Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury [see Drug Interactions (7.3)].

5.6 Electrolyte Effects

Piperacillin and tazobactam for injection contains a total of 2.43 mEq (56 mg) of Na

+per gram of piperacillin and tazobactam in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.

5.7
Clostridium Difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including piperacillin and tazobactam for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of

C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of

C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against

C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.8 Development Of Drug-Resistant Bacteria

Prescribing piperacillin and tazobactam for injection in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.During the initial clinical investigations, 2621 patients worldwide were treated with piperacillin and tazobactam for injection in phase 3 trials. In the key North American monotherapy clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3.2% of the patients treated worldwide, piperacillin and tazobactam for injection was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%).Table 3: Adverse Reactions from Piperacillin and Tazobactam for Injection Monotherapy Clinical Trials System Organ Class Adverse Reaction Gastrointestinal disorders Diarrhea (11.3%) Constipation (7.7%) Nausea (6.9%) Vomiting (3.3%) Dyspepsia (3.3%) Abdominal pain (1.3%)General disorders and administration site conditions Fever (2.4%) Injection site reaction (1%) Rigors (1%) Immue system disorders Anaphylaxis (1%)Infections and infestations Candidiasis (1.6%) Pseudomembranous colitis (1%)Metabolism and nutrition disorders Hypoglycemia (1%)Metabolism and connective tissue disorders Hypoglycemia (1%)Muscoloskeletal and connective tissue disorders Myalgia (1%) Arthralgia (1%)Nervous System Disorders Headache (7.7%)Psychiatric disorders Insomnia (6.6%)Skin and subcutaneous tissue disorders Rash (4.2%, including maculopapular, bullous, and urticarial) Pruritus (3.1%) Purpura (1%)Vascular disorders Phlebitis (1.3%) Thrombophlebitis (1%) Hypotension (1%) Flushing (1%)Respiratory, thoracic and mediastinal disorders Epistaxis (1%)Nosocomial Pneumonia TrialsTwo trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with piperacillin and tazobactam for injection in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg q6h) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin/tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0%) patients in the piperacillin/tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event.The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside.Table 4: Adverse Reactions from Piperacillin and Tazobactam for Injection Plus Aminoglycoside Clinical Trials

​aSystem Organ Class Adverse Reactiona For adverse drug reactions that appeared in both studies the higher frequency is presented.

PediatricsStudies of piperacillin and tazobactam for injection in pediatric patients suggest a similar safety profile to that seen in adults. In a prospective, randomized, comparative, open-label clinical trial of pediatric patients with severe intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with piperacillin and tazobactam for injection (112.5 mg/kg every 8 hours) and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the piperacillin and tazobactam for injection group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the piperacillin and tazobactam for injection group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event.Adverse Laboratory Events (Seen During Clinical Trials)Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of piperacillin and tazobactam for injection was used in combination with an aminoglycoside, changes in laboratory parameters include:Hematologic - decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills).

Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyltransferase increased, hypokalemia, and bleeding time prolonged.

6.2 Post-Marketing Experience

In addition to the adverse drug reactions identified in clinical trials in Table 3 and Table 4, the following adverse reactions have been identified during post approval use of piperacillin and tazobactam for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hepatobiliary – hepatitis, jaundice

The following adverse reaction has also been reported for piperacillin for injection:Skeletal—prolonged muscle relaxation [

see

Drug Interactions (7.5)].

Post-marketing experience with piperacillin and tazobactam for injection in pediatric patients suggests a similar safety profile to that seen in adults.

7.1 Aminoglycosides

Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides.In vivo inactivation

:When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored.

Sequential administration of piperacillin and tazobactam for injection and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary.In vitro Inactivation:

Due to the

in vitro inactivation of aminoglycosides by piperacillin, piperacillin and tazobactam for injection and aminoglycosides are recommended for separate administration. Piperacillin and tazobactam for injection and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. Piperacillin and tazobactam for injection is not compatible with tobramycin for simultaneous Y-site infusion [

see Dosage and Administration (

2.7)

].

7.2 Probenecid

Probenecid administered concomitantly with piperacillin and tazobactam for injection prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam. Probenecid should not be co-administered with piperacillin and tazobactam for injection unless the benefit outweighs the risk.

7.3 Vancomycin

Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone [see

No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin.

7.4 Anticoagulants

Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function. [see

Warnings and Precautions (5.3)]

7.5 Vecuronium

Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Piperacillin and tazobactam for injection could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the nondepolarizing muscle relaxants could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade (See package insert for vecuronium bromide).

7.6 Methotrexate

Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored.

7.7 Effects On Laboratory Tests

There have been reports of positive test results using the Bio-Rad Laboratories

Platelia Aspergillus EIA test in patients receiving piperacillin/tazobactam injection who were subsequently found to be free of

Aspergillus infection. Cross-reactions with non-

Aspergillus Polysaccharides and Polyfuranoses with the Bio-Rad Laboratories Platelia

Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin/tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.

As with other penicillins, the administration of piperacillin and tazobactam for injection may result in a false-positive reaction for glucose in the urine using a copper-reduction method (CLINITEST

®). It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

8.1 Pregnancy

Risk SummaryPiperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. No fetal structural abnormalities were observed in rats or mice when piperacillin/tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m

2). However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m

2)

[see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataIn embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin/tazobactam up to 3000/750 mg/kg/day during the period of organogenesis. There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m

2). Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m

2).

A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥640/160 mg/kg/day piperacillin/tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area).Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin/tazobactam at doses ≥640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21.

8.2 Lactation

Risk SummaryPiperacillin is excreted in human milk; tazobactam concentrations in human milk have not been studied. No information is available on the effects of piperacillin and tazobactam on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for piperacillin and tazobactam for injection and any potential adverse effects on the breastfed child from piperacillin and tazobactam for injection or from the underlying maternal condition.

8.4 Pediatric Use

Use of piperacillin and tazobactam for injection in pediatric patients 2 months of age or older with appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. This includes a prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients 2–12 years of age with complicated intra-abdominal infections, in which 273 pediatric patients received piperacillin/tazobactam. Safety and efficacy in pediatric patients less than 2 months of age have not been established [

see Clinical Pharmacology (

12) and Dosage and Administration (

2)

].

It has not been determined how to adjust piperacillin and tazobactam for injection dosage in pediatric patients with renal impairment.

8.5 Geriatric Use

Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal impairment [

see Dosage and Administration (

2)

].

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.Piperacillin and tazobactam for injection contains 56 mg (2.43 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients would receive between 672 and 896 mg/day (29.16 and 38.88 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading.This may be clinically important with regard to such diseases as congestive heart failure. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Impairment

In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for injection should be reduced to the degree of renal function impairment [

see Dosage and Administration (

2)

].

8.7 Hepatic Impairment

Dosage adjustment of piperacillin and tazobactam for injection is not warranted in patients with hepatic cirrhosis [See

Clinical Pharmacology (12.3)].

8.8 Patients With Cystic Fibrosis

As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

10 Overdosage

There have been post-marketing reports of overdose with piperacillin/tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure)

[see Warnings and Precautions (5.4)].

Treatment should be supportive and symptomatic according the patient’s clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin/tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively

[see Clinical Pharmacology (12)].

11 Description

Piperacillin and tazobactam for injection is an injectable antibacterial combination product consisting of the semisynthetic antibacterial piperacillin sodium and the β-lactamase inhibitor tazobactam sodium for intravenous administration.Piperacillin sodium is derived from D(-)-α-aminobenzyl-penicillin. The chemical name of piperacillin sodium is sodium (2

S,5

R,6

R)-6-[(

R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate. The chemical formula is C

23H

26N

5NaO

7S and the molecular weight is 539.5. The chemical structure of piperacillin sodium is:

Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2

S,3

S,5

R)-3-methyl-7-oxo-3-(1

H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C

10H

11N

4NaO

5S and the molecular weight is 322.3. The chemical structure of tazobactam sodium is:

Piperacillin and Tazobactam for Injection is a white to off-white sterile powder consisting of piperacillin and tazobactam as their sodium salts packaged in glass vials.Each Piperacillin and Tazobactam for Injection 13.5 g pharmacy bulk vial contains piperacillin sodium equivalent to 12 grams of piperacillin and tazobactam sodium equivalent to 1.5 g of tazobactam sufficient for delivery of multiple doses.Each Piperacillin and Tazobactam for Injection 40.5 g pharmacy bulk vial contains piperacillin sodium equivalent to 36 grams of piperacillin and tazobactam sodium equivalent to 4.5 g of tazobactam sufficient for delivery of multiple doses.Piperacillin and Tazobactam for Injection contains a total of 2.43 mEq (56 mg) of sodium (Na

+) per gram of piperacillin in the combination product.

12.1 Mechanism Of Action

Piperacillin and tazobactam for injection is an antibacterial drug [

see Microbiology (12.4)

].

12.2 Pharmacodynamics

The pharmacodynamic parameter for piperacillin/tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC.

12.3 Pharmacokinetics

The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam for injection after multiple intravenous doses are summarized in Table 6.Table 6: Mean (CV%) Piperacillin and Tazobactam for Injection PK Parameters a Piperacillin and tazobactam were given in combination, infused over 30 minutes

RmL/min 2.25 g1516.0 (21)25817.0 0.77- 3.375 g 24 25.0 (8) 251 14.8 0.68 166 4.5 g 34 39.8 (15) 206 14.7 0.82 -Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of piperacillin and tazobactam for injection. Piperacillin plasma concentrations, following a 30-minute infusion of piperacillin and tazobactam for injection, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose due to the short half-lives of piperacillin and tazobactam.DistributionBoth piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 7). Table 7: Piperacillin/Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of Piperacillin and Tazobactam for Injectiona Each subject provided a single sample

b Time from start of the infusion

Tissue orFluid N

aSamplingperiod

b(h) Mean PIPConcentrationRange(mg/L)Tissue:PlasmaRangeTazoConcentrationRange(mg/mL)Tazo Tissue:Plasma RangeSkin 35 0.5-4.5 34.8-94.2 0.6-1.1 4.0-7.70.49-0.93Fatty Tissue 37 0.5-4.5 4.0-10.1 0.097-0.115 0.7-1.5 0.10-0.13Muscle 36 0.5-4.5 9.4-23.3 0.29-0.18 1.4-2.7 0.18-0.30ProximalIntestinalMucosa 7 1.5-2.5 31.4 0.55 10.3 1.15DistalIntestinalMucosa 7 1.5-2.5 31.2 0.59 14.5 2.1Appendix 22 0.5-2.5 26.5-64.1 0.43-0.53 9.1-18.6 0.80-1.35MetabolismPiperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities.ExcretionFollowing single or multiple piperacillin and tazobactam for injection doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion.Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile.Specific PopulationsRenal ImpairmentAfter the administration of single doses of piperacillin/tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for piperacillin and tazobactam for injection are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of piperacillin and tazobactam for injection.

See Dosage and Administration (2) for specific recommendations for the treatment of patients with renal impairment.

Hemodialysis removes 30% to 40% of a piperacillin/tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite.For dosage recommendations for patients undergoing hemodialysis [

see Dosage and Administration (2)].

Hepatic ImpairmentThe half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of piperacillin and tazobactam for injection due to hepatic cirrhosis.PediatricsPiperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults.In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 29 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin distribution volume is 0.243 (0.011) L/kg and is independent of age.GeriatricsThe impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18 - 35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacillin and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance.RaceThe effect of race on piperacillin and tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses.Drug InteractionsThe potential for pharmacokinetic drug interactions between piperacillin and tazobactam for injection and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [

In vitro, piperacillin is active against a variety of Gram-positive and Gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant

in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a β-lactamase inhibitor of the Molecular Class A Enzymes, including Richmond-Sykes Class III (Bush Class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated β-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.

Spectrum of ActivityPiperacillin/tazobactam has been shown to be active against most isolates of the following microorganisms both

(given in combination with an aminoglycoside to which the isolate is susceptible)

Anaerobic bacteria:

Bacteroides fragilis

group (

B. fragilis, B. ovatus, B. thetaiotaomicron, and

B. vulgatus)

The following

in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit an

in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin/tazobactam. However, the safety and effectiveness of piperacillin/tazobactam in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria:

Enterococcus faecalis

(ampicillin or penicillin-susceptible isolates only)

Staphylococcus epidermidis

(methicillin susceptible isolates only)

Streptococcus agalactiae

† Streptococcus pneumoniae

† (penicillin-susceptible isolates only)

Streptococcus pyogenes

†Viridans group streptococci

†Gram-negative bacteria:

Citrobacter koseri

Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

Providencia stuartii

Providencia rettgeri

Salmonella enterica

Anaerobic bacteria:

Clostridium perfringens

Bacteroides distasonis

Prevotella melaninogenica

†These are not β-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone.

Long-term carcinogenicity studies in animals have not been conducted with piperacillin/tazobactam, piperacillin, or tazobactam.Piperacillin/TazobactamPiperacillin/tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese Hamster Ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay.

In vivo, piperacillin/tazobactam did not induce chromosomal aberrations in rats.

Piperacillin/TazobactamReproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin/tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin/tazobactam, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m

Serious Hypersensitivity ReactionsAdvise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur that require immediate treatment. Ask them about any previous hypersensitivity reactions to piperacillin and tazobactam for injection, other beta-lactams (including cephalosporins), or other allergens [

see Warnings and Precautions (5.2)].

DiarrheaAdvise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug. If this occurs, patients should contact their physician as soon as possible.Antibacterial ResistanceCounsel patients that antibacterial drugs including piperacillin and tazobactam for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When piperacillin and tazobactam for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by piperacillin and tazobactam for injection or other antibacterial drugs in the future.Counsel patients that piperacillin and tazobactam for injection can cross the placenta in humans and is excreted in human milk.For all questions concerning adverse reactions associated with the use of this product or for inquiries concerning our products, please contact 1-833-727-6556.Distributed by:Apollo Pharmaceuticals USA Inc.

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